Process for the production of 2-fluoroisobutyric acid or its ester

ABSTRACT

Provided is a process for the production of 2-fluoroisobutyric acid or its ester, which comprises reacting 2-hydroxyisobutyric acid or its ester with thionyl chloride and a hydrogen fluoride source.

This application is a 371 of PCT/JP94/ 00588, filed April 07, 1994

FILED OF INDUSTRIAL UTILIZATION

The present invention relates to a process for the production of2-fluoroisobutyric acid or an ester thereof. The 2-fluoroisobutyric acidor the ester thereof, obtained by the present invention, is useful as anintermediate for a triazine-based herbicide.

PRIOR ART

As a triazine-based herbicide, International PCT Publication W090/09378discloses a triazine-based herbicide in which a phenoxyalkylamino groupis substituted on a triazine ring, for example, as shown by the formula,##STR1## and this Publication describes that the above triazine-basedherbicide has remarkable advantages in that it is not only excellent inherbicidal activity but also free from phytotoxicity to rice on a paddyfield.

The phenoxyalkylamino-substituted triazine-based herbicide of this typeis obtained by reacting 2-fluoroisobutyrate with2-phenoxy-1-methyl-ethylbiguanide. As a method for producing2-fluoroisobutyrate used in the above reaction, U.S. Pat. No. 5,175,345discloses a method in which 2-hydroxyisobutyrate is reacted (a) withfluorosulfuric acid in the presence or absence of a hydrogen fluoridesource or (b) with chlorosulfuric acid in the presence of hydrogenfluoride. This conventional method is shown by a reaction scheme below.##STR2##

PROBLEMS TO BE SOLVED BY THE INVENTION

In the method using 2-hydroxyisobutyrate as a raw material, described inthe above U.S. Patent, 2-fluoroisobutyrate can be obtained at relativelyhigh yields, while a large amount of methacrylate having a boiling pointclose to that of the 2- fluoroisobutyrate is formed as a byproduct.Industrially disadvantageously, therefore, the post treatment forremoving the methacrylate formed as a byproduct is complicated. Forachieving high yields, further, a large amount (at least 6 mol per moleof the raw material) of fluorosulfuric acid is required, and it isrequired to neutralize unreacted fluorosulfuric acid with an alkali suchas Ca(OH)₂ before disposal. There is hence another defect in that alarge amount of waste is formed.

It is therefore an object of the present invention to provide a processwhich enables the production of 2-fluoroisobutyric acid or its ester ina simple apparatus at high yields while preventing the formation of abyproduct which is difficult to separate.

MEANS TO SOLVE THE PROBLEMS

The present inventors have found that, by reacting 2-hydroxyisobutyricacid or its ester with thionyl chloride and a hydrogen fluoride source,2-fluoroisobutyric acid or its ester can be produced in a simpleapparatus at high yields while preventing the formation of a byproduct,and on basis of this finding, the present invention has been completed.

The object of the present invention therefore consists in a process forthe production of 2-fluoroisobutyric acid or its ester, which comprisesreacting 2-hydroxyisobutyric acid or its ester with thionyl chloride anda hydrogen fluoride source.

The present invention will be detailed hereinafter.

In the process for the production of 2-fluoroisobutyric acid or itsester, provided by the present invention, the 2-ydroxyisobutyric acid orits ester used as a starting material includes, for example, compoundsof the general formula (I), ##STR3## (wherein R is a hydrogen atom or alower alkyl group).

The compound of the general formula (I) in which R is a hydrogen atom is2-hydroxyisobutyric acid, and the compound of the general formula (I) inwhich R is a lower alkyl group is 2-hydroxyisobutyrate. The alkyl groupfor R includes alkyl groups having to 1 to 4 carbon atoms such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl andt-butyl groups.

According to the present invention, the above 2-ydroxyisobutyric acid orits ester is reacted with thionyl chloride and a hydrogen fluoridesource, whereby 2-fluoroisobutyric acid or its ester is obtained.

The raw material for the reaction in the present invention is2-hydroxyisobutyric acid or its ester, while 2-hydroxyisobutyric acidester is preferred. The reason therefor is that the ester can give afluorinated product at higher yields.

When 2-hydroxyisobutyric acid or its ester is allowed to react withthionyl chloride and a hydrogen fluoride source, it is preferred toreact the 2-hydroxyisobutyric acid or its ester with thionyl chloridefirst and then with a hydrogen fluoride source.

The method for reacting 2-hydroxyisobutyric acid or its ester withthionyl chloride and then with a hydrogen fluoride source will beexplained.

The reaction of 2-hydroxyisobutyric acid or its ester with thionylchloride in a first step is carried out by adding thionyl chloride to2-hydroxyisobutyric acid or its ester and stirring the mixture, or byadding 2-hydroxyisobutyric acid or its ester to thionyl chloride andstirring the mixture. In this reaction, it is preferred to use thionylchloride in an amount of 0.5 to 5 mol per mole of the2-hydroxyisobutyric acid or its ester, and particularly preferably, themolar amount of thionyl chloride is 0.8 to 1.5 times as large as themolar amount of the 2-hydroxyisobutyric acid or its ester.

The reaction temperature is preferably -30 to 50° C., particularlypreferably -20 to 20° C. The reaction time is preferably 0.5 to 10hours, particularly preferably 1 to 5 hours.

In the above reaction in the first step, a solvent is not essential,while an organic solvent inert to the above reactants may be used. Theorganic solvent includes a saturated aliphatic or aromatic hydrocarbon,a saturated aliphatic or aromatic halogenated hydrocarbon, and asaturated aliphatic or aromatic ester.

The reaction with a fluoride source in a second step is carried out bymixing chlorosulfite (corresponding to an intermediate for the intendedcompound, 2-fluoroisobutyric acid or its ester) as a reaction product inthe reaction mixture obtained in the first step with a hydrogen fluoridesource without or after isolating the chlorosulfite. The mixing of thesetwo is carried out by adding the above reaction mixture or the isolatedreaction product to a hydrogen fluoride Source, or, reversely, by addinga hydrogen fluoride source to the above reaction mixture or the isolatedreaction product.

The hydrogen fluoride source is selected from anhydrous hydrogenfluoride and a mixture of hydrogen fluoride with an amine. The hydrogenfluoride/amine amount ratio in the above mixture is preferably 50/50 to99/1 (w/w). The above amine includes aromatic amines such as pyridine,melamine and collidine and tertiary aliphatic amines such astrimethylamine, triethylamine and tributylamine. The above hydrogenfluoride source is only required to be in the state of hydrogen fluorideat the time of the reaction, and therefore, a hydrogen fluorideprecursor may be charged to the reaction system to generate hydrogenfluoride in the reaction system.

In the above reaction in the second step, the amount of the hydrogenfluoride per mole of 2-hydroxyisobutyric acid or its ester is preferably1 to 50 mol, more preferably 5 to 30 mol, particularly preferably 7 to15 mol. The amount of the hydrogen fluoride is most preferably 10 mol,or about 10 mol, per mole of 2-hydroxyisobutyric acid or its ester.

The temperature when the mixture with hydrogen fluoride is formed ispreferably -78 to 10° C., particularly preferably -78 to 0° C., mostpreferably -78° C. to -10° C.

The reaction temperature after the mixture with hydrogen fluoride isformed is preferably -30 to 100° C., particularly preferably -20 to 50°C., and the reaction time is preferably 0.5 to 30 hours, particularlypreferably 1 to 20 hours.

In the above reaction in the second step, a solvent is not essential,either, while there may be used an inert solvent such as a saturatedaliphatic or aromatic hydrocarbon, a saturated aliphatic or aromatichalogenated hydrocarbon, or a saturated aliphatic or aromatic ester. Itis preferred to use solvents of the same kind as a solvent for thereaction in the first step and the reaction in the second step.

After the reaction in the second step is completed, the intendedcompound, 2-fluoroisobutyric acid or its ester, is isolated from thereaction mixture by a known method. When solvent extraction is used as amethod for the isolation, methylene chloride is a preferred solvent.

The reactions in the first and second step may be carried out underatmospheric pressure or under elevated pressure.

The foregoing description has explained a method in which thionylchloride is reacted first and then the hydrogen fluoride source isadded. However, thionyl chloride and the hydrogen fluoride source may besimultaneously added and reacted.

According to the process of the present invention, 2-hydroxyisobutyricacid or its ester is used as a raw material, and 2-fluoroisobutyric acidor its ester can be produced in a simple apparatus at high yields whilepreventing the formation of a byproduct. Therefore, the presentinvention has industrially great significance.

EXAMPLES

The present invention will be further explained hereinafter withreference to Examples. However, the present invention shall not belimited to these Examples.

Example 1

A reactor made of glass was charged with 10.70 g (90.7 mmol) of methyl2-hydroxyisobutyrate, and 11.47 g (96.4 mmol) of thionyl chloride wasdropwise added with ice cooling. After the dropwise addition wascompleted, the mixture was stirred for 3 hours with ice cooling, duringwhich the reaction mixture had a temperature of 0 to 10° C. A reactormade of stainless steel was flushed with argon, and then charged with18.7 g (935 mmol) of anhydrous hydrogen fluoride, and the above reactionmixture was dropwise added at -10° C. After the addition, the reactorwas sealed, and the mixture was stirred at 20° C. for 18 hours.

The resultant reaction mixture was poured onto ice, and extracted withmethylene chloride. An organic layer was washed with water, a sodiumhydrogencarbonate aqueous solution and a saturated sodium chlorideaqueous solution in this order, and then dried over anhydrous sodiumsulfate. Methylene chloride was distilled off under reduced pressure,and then the remainder was distilled to give 7.90 g (yield 73% of methyl2-fluoroisobutyrate having a boiling point of 70° C. (150 mmHg). Theamount of methyl methacrylate formed as a byproduct was 0.7%.

Example 2

The reactions in Example 1 were repeated in the same manner as inExample 1 except that the amount of methyl 2-hydroxyisobutyrate waschanged to 10.29 g (87.1 mmol) and that the amount of anhydrous hydrogenfluoride was changed to 9.1 g (455 mmol). As a result, 7.22 g (yield69%) of methyl 2-fluoroisobutyrate was obtained. The amount of methylmethacrylate formed as a byproduct was 3.9%.

Example 3

A reactor made of glass was charged with 11.40 g (95.8 mmol) of thionylchloride, and 10.25 g (86.9 mmol) of methyl 2-hydroxyisobutyrate wasdropwise added with ice cooling. After the dropwise addition wascompleted, the mixture was stirred for 3 hours with ice cooling, duringwhich the reaction mixture had a temperature of 0 to 10° C. A reactormade of stainless steel was flushed with argon, and then charged with17.5 g (875 mmol) of anhydrous hydrogen fluoride, and the above reactionmixture was dropwise added at -10° C. After the addition, the reactorwas sealed, and the mixture was stirred at 20° C. for 18 hours.

The resultant reaction mixture was poured onto ice, and extracted withmethylene chloride. An organic layer was washed with water, a sodiumhydrogencarbonate aqueous solution and a saturated sodium chlorideaqueous solution in this order, and then dried over anhydrous sodiumsulfate. Methylene chloride was distilled off under reduced pressure,and then the remainder was distilled to give 7.80 g (yield 74% of methyl2-fluoroisobutyrate having a boiling point of 70° C. (150 mmHg). Theamount of methyl methacrylate formed as a byproduct was 2.1%.

Examples 4-16

Methyl 2-fluoroisobutyrate was obtained in the same manner as in Example3 except that the amounts of methyl 2-hydroxyisobutyrate, thionylchloride and anhydrous hydrogen fluoride were set as shown in thefollowing Table 1, and that the temperature when a reaction mixture ofthe methyl 2-hydroxyisobutyrate and thionyl chloride was added to theanhydrous hydrogen fluoride and the temperature and time for thereaction with the anhydrous hydrogen fluoride were changed as shown inTable 1. Table 1 shows the yield of the methyl 2-fluoroisobutyrate andthe amount of methyl methacrylate formed as a byproduct.

                                      TABLE 1                                     __________________________________________________________________________                                    Temperature                                                                            Temperature                                                                             Yield of                   Amount [g (mmol)]               at the time of                                                                         and time for                                                                            methyl                                                                             Amount of             Exam-                                                                             (A) Methyl       (C) Anhydrous                                                                            addition to                                                                            reaction with                                                                           2-fluoro                                                                           methyl                ple 2-hydroxy-                                                                           (B) Thionyl                                                                          (B)/                                                                             hydrogen                                                                              (C)/                                                                             anhydrous                                                                              anhydrous isobuty-                                                                           methacrylate          No. isobutyrate                                                                          chloride                                                                             (A)                                                                              fluoride                                                                              (A)                                                                              hydrogen fluoride                                                                      hydrogen fluoride                                                                       rate as                    __________________________________________________________________________                                                            byproduct             1   10.70                                                                            (90.7)                                                                            11.47                                                                            (96.4)                                                                            1.06                                                                             18.7                                                                             (935)                                                                              10.30                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            73%  0.7%                  2   10.29                                                                            (87.1)                                                                            11.47                                                                            (96.4)                                                                            1.11                                                                             9.1                                                                              (455)                                                                               5.22                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            69%  3.9%                  3   10.25                                                                            (86.9)                                                                            11.4                                                                             (95.8)                                                                            1.10                                                                             17.5                                                                             (875)                                                                              10.06                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            74%  2.1%                  4   10.25                                                                            (86.9)                                                                            13.1                                                                             (110)                                                                             1.27                                                                             16.1                                                                             (805)                                                                               9.26                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            80%  3.1%                  5   10.73                                                                            (90.9)                                                                            14.2                                                                             (119)                                                                             1.31                                                                             17.4                                                                             (870)                                                                               9.57                                                                            -40° C.                                                                         20° C.,                                                                    18 hours                                                                            81%  1.3%                  6   10.16                                                                            (86.1)                                                                            13.1                                                                             (110)                                                                             1.28                                                                             17.4                                                                             (870)                                                                              10.10                                                                            -78° C.                                                                         20° C.,                                                                    18 hours                                                                            81%  1.3%                  7   10.38                                                                            (88.0)                                                                            15.7                                                                             (132)                                                                             1.50                                                                             19.3                                                                             (965)                                                                              10.09                                                                            -78° C.                                                                         20° C.,                                                                     5 hours                                                                            73%  1.2%                  8   5.04                                                                             (42.7)                                                                            7.1                                                                              (59.7)                                                                            1.40                                                                             13.9                                                                             (695)                                                                              16.27                                                                            -40° C.                                                                         30° C.,                                                                     2 hours                                                                            77%  2.1%                  9   5.02                                                                             (42.5)                                                                            7.1                                                                              (59.7)                                                                            1.40                                                                             11.0                                                                             (550)                                                                              12.94                                                                            -40° C.                                                                         30° C.,                                                                     5 hours                                                                            79%  1.2%                  10  5.05                                                                             (42.8)                                                                            7.3                                                                              (61.3)                                                                            1.43                                                                             10.7                                                                             (535)                                                                              12.50                                                                            -40° C.                                                                         40° C.,                                                                     2 hours                                                                            77%  3.7%                  11  9.99                                                                             (84.7)                                                                            11.5                                                                             (96.6)                                                                            1.14                                                                             17.8                                                                             (890)                                                                              10.51                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            79%  1.3%                                                           30° C.,                                                                     2 hours*)                       12  5.01                                                                             (42.5)                                                                            7.0                                                                              (58.8)                                                                            1.38                                                                             27.5                                                                             (1,375)                                                                            32.35                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            78%  1.5%                  13  5.04                                                                             (42.7)                                                                            7.0                                                                              (58.8)                                                                            1.38                                                                             16.4                                                                             (820)                                                                              19.20                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            75%  1.5%                  14  5.00                                                                             (42.4)                                                                            7.0                                                                              (58.8)                                                                            1.39                                                                             9.7                                                                              (485)                                                                              11.44                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            77%  1.6%                  15  10.20                                                                            (86.4)                                                                            13.1                                                                             (110)                                                                             1.27                                                                             17.7                                                                             (885)                                                                              10.24                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            84%  2.8%                  16  10.08                                                                            (85.4)                                                                            11.7                                                                             (98.3)                                                                            1.15                                                                             5.7                                                                              (285)                                                                               3.33                                                                            -10° C.                                                                         20° C.,                                                                    18 hours                                                                            80%  7.2%                  __________________________________________________________________________     (B)/(A) and (C)/(A) refer to molar ratios of thionyl chloride and             anhydrous hydrogen fluoride to methyl 2hydroxy-isobutyrate.                   *) Reacted at 20° C. for 18 hours, and further reacted at              30° C. for 2 hours.                                               

Table 1 shows the following.

(i) On basis of the results of Examples 1 to 16 in which the amount ofanhydrous hydrogen fluoride based on the methyl 2-hydroxyisobutyrate wasvaried, when the amount of anhydrous hydrogen fluoride based on methyl2-hydroxyisobutyrate is small, as small as 3.33 mol and 5.22 mol permole of the methyl 2-hydroxyisobutyrate in Examples 16 and 2, the amountof methyl methacrylate formed as a byproduct is large, as large as 7.2%and 3.9%. In contrast, when the amount of anhydrous hydrogen fluorideper mole of methyl 2-hydroxyisobutyrate is 10 mol or in the vicinity of10 mol, for example, in Examples 1, 6 and 11, the yield of the intendedproduct is high, and the amount of methyl methacrylate formed as abyproduct is small, as small as 0.7%, 1.3% and 1.3%. Even if the amountof anhydrous hydrogen fluoride per mole of 2-hydroxyisobutyrate isincreased, for example, to 16.27 mol (Example 8) or 19.20 mol (Example13), the yield of the intended product and the amount of the byproducthardly change as compared with a case where the above amount per mole of2-hydroxyisobutyrate is 10 mol or in the vicinity of 10 mol.

(ii) On the basis of the results of Examples 4, 5 and 6 in which thetemperature at the time of the addition to anhydrous hydrogen fluoridewas set at -10° C., -40° C. and -78° C., respectively, so long as thetemperature at the time of the addition to anhydrous hydrogen fluorideis -10° C. or lower, the yield of methyl 2-fluoroisobutyrate is 80 to81%, or hardly varies. However, when this temperature is -40° C. orlower, the amount of methyl methacrylate formed as a byproduct is small.

(iii) On the basis of the results of Examples 6-11 in which thetemperature and time for the reaction with anhydrous hydrogen fluoridewere changed, when the temperature is 20° C. and when a short reactiontime is employed, the yield of the intended product is low to someextent (in Example 6 where the reaction temperature and times are 20° C.and 18 hours, the yield of the intended product is 81%, while in Example7 where the reaction temperature and time are 20° C. and 5 hours, theyield of the intended product is 73%). However, if it is considered thatthe short reaction time is employed, this yield is to be satisfactory.When the reaction temperature is increased from 20° C. to 30° C. or 40°C., the amount of methyl methacrylate formed as a byproduct increases(in Example 7 where the reaction temperature and time are 20° C. and 5hours, the amount of the byproduct is 1.2%, while in Example 8 where thereaction temperature and time are 30° C. for 2 hours, the amount of thebyproduct is 2.1%, and in Example 10 where the reaction temperature andtime are 40° C. and 2 hours, the amount of the byproduct is 3.7%).

Comparative Example 1

Example 7 of U. S. Pat. No. 5,175,345 was repeated.

That is, 13.2 g of a hydrogen fluoride (HF)/pyridine (Py) mixture (HF/Py=95/5 (wt/wt), containing about 627 mmol of the hydrogen fluoride) and19.3 g (193 mmol) of fluorosulfuric acid were charged into a 50 mlautoclave having an internal cylinder made of Teflon, and cooled to 0°C. 3.6 Grams (30.5 mmol) of methyl 2-hydroxyisobutyrate was added, andthen, the mixture was heated to 20° C. and allowed to react for 18hours. After the reaction finished, the reaction mixture was poured intoice water and extracted with methylene chloride. A methylene chlorideextract was dried over anhydrous sodium sulfate, and then methylenechloride was distilled off. The remainder was distilled to give 2.67 g(yield 73%) of methyl 2-fluoroisobutyrate having a boiling point of 70°C. (150 mmHg). The so-obtained methyl 2-fluoroisobutyrate had a boilingpoint under atmospheric pressure of 106° to 107° C. It was found thatmethyl methacrylate was formed as a byproduct in an amount of as much as8%.

When the above Examples 1 to 16 and Comparative Example 1 are compared,it is clearly seen that, according to the process of the presentinvention, 2-fluoroisobutyric acid or its ester can be obtained at highyields while preventing the formation of MMA as a byproduct as comparedwith the process described in U. S. Pat. No. 5,175,345 which is a priorart.

Effect of the Invention

As described above, according to the present invention, there isprovided a process which enables the production of 2-fluoroisobutyricacid or its ester in a simple apparatus at high yields while preventingthe formation of a byproduct.

We claim:
 1. A process for the production of 2-fluoroisobutyric acid orits ester, which comprises reacting 2-hydroxyisobutyric acid or itsester with thionyl chloride and a hydrogen fluoride source.
 2. Theprocess according to claim 1, wherein the 2-hydroxyisobutyric acid orits ester is reacted with the thionyl chloride, and then a reactionmixture is reacted with the hydrogen fluoride source.
 3. The processaccording to claim 2, wherein the 2-hydroxyisobutyric acid ester isreacted with the thionyl chloride, and then the reaction mixture isreacted with the hydrogen fluoride source to obtain 2-fluoroisobutyricacid ester.
 4. The process according to any one of claims 1 to 3,wherein the thionyl chloride is used in an amount of 0.5 to 5 mol permole of the 2-hydroxyisobutyric acid or its ester.
 5. The processaccording to claim 4, wherein the thionyl chloride is used in an amountof 0.8 to 1.5 mol per mole of the 2-hydroxyisobutyric acid or its ester.6. The process according to any one of claims 1 to 3, wherein thehydrogen fluoride source comprises hydrogen fluoride or a mixture ofhydrogen fluoride with an amine.
 7. The process according to any one ofclaims 1 to 3, wherein the hydrogen fluoride source is used which iscapable of generating hydrogen fluoride in an amount of 1 to 50 mol permole of the 2-hydroxyisobutyric acid or its ester.
 8. The processaccording to claim 7, wherein the hydrogen fluoride source is used whichis capable of generating hydrogen fluoride in an amount of 5 to 30 molper mole of the 2-hydroxyisobutyric acid or its ester.
 9. The processaccording to claim 8, wherein the hydrogen fluoride source is used whichis capable of generating hydrogen fluoride in an amount of 7 to 15 molper mole of the 2-hydroxyisobutyric acid or its ester.